US2016038651A1PendingUtilityA1
Compounds and compositions for drug release
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
A61P 31/04A61L 31/16A61L 31/06A61L 27/54A61L 2420/02A61L 2300/406A61L 29/085A61L 2300/41A61L 29/08A61L 27/34A61L 31/08A61L 31/10A61L 2300/80A61L 29/16
44
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Claims
Abstract
The invention relates to compounds that include biologically active agents (e.g., compounds according to any of formulas (I) and (I-A) that can be used for effective drug release, e.g., as coatings for medical devices. Use of these compounds in the coating of surfaces can allow for long-term drug release as well as imparting uniform coatings with little phase separation compared to, e.g., the parent biologically active agent.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An article comprising a coated surface, wherein said coated surface comprises a compound having a structure according to formula (I):
Bio 1 -Link 1 -(Bio 2 -R 1 ) m (I),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; m is 1, 2, 3, 4, or 5; each Bio 2 is absent or independently formed from a biologically active agent, and wherein each Bio 2 , when present, comprises a covalent bond to Link 1 ; R 1 is present only when Bio 2 is absent and is a terminal group selected from the group consisting of H, OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons.
2 . The article of claim 1 , wherein said compound has a structure according to formula (I-A),
Bio 1 -Link 1 -Bio 2 -R 1 (I-A),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; Bio 2 is absent or formed from a biologically active agent; R 1 , when present, is H, OH, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; and Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons.
3 . The article of claim 1 or 2 , wherein Bio 2 is absent.
4 . The article of claim 1 or 2 , wherein Bio 2 is present.
5 . The article of claim 4 , wherein Bio 1 and Bio 2 are formed from biologically active agents that have the same structure.
6 . The article of claim 5 , wherein Bio 1 and Bio 2 are formed from biologically active agents that have different structures.
7 . The article of any one of claims 1 - 6 , wherein each Bio 1 and Bio 2 , when present, has a molecular weight ranging from 100 to 1000, from 200 to 1000, from 200 to 900, from 200 to 800, from 200 to 700, from 200 to 600, from 200 to 500, or from 200 to 400 Daltons.
8 . The article of any one of claims 1 - 7 , wherein each Bio 1 and Bio 2 , when present, is formed from a biologically active agent selected from the group consisting of: anti-inflammatory agents, anti-thrombotic agents; anti-oxidant agents, anti-coagulant agents, anti-microbial agents, anti-proliferative agents, cell receptor ligands, and bio-adhesive molecules.
9 . The article of claim 8 , wherein one or both of Bio 1 and Bio 2 , when present, is formed from an anti-microbial agent.
10 . The article of claim 8 or 9 , wherein one or both of Bio 1 and Bio 2 , when present, is independently, is formed from an antibiotic.
11 . The article of claim 10 , wherein said antibiotic is a fluoroquinolone antibiotic.
12 . The article of claim 11 , wherein said antibiotic is selected from the group consisting of: norfloxancin, oflxacin, ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin.
13 . The article of claim 12 , wherein said antibiotic is ciprofloxacin.
14 . The article of any one of claims 1 - 6 , wherein one or both of Bio 1 and Bio 2 is a protein or a peptide.
15 . The article of any one of claims 1 - 14 , wherein Link 1 has a molecular weight between 60 and 700 Daltons.
16 . The article of any one of claims 1 - 15 , wherein Link 1 is formed from a diol, a diamine, or an α,ω-aminoalcohol.
17 . The article of claim 16 , wherein Link 1 is formed from a diol.
18 . The article of claim 16 , wherein Link 1 is formed from a polyethylene oxide having terminal amino or hydroxyl groups, and wherein Link1 comprises 1-3, 1-5, 1-10, or 1-20 ethylene oxide repeating units.
19 . The article of claim 16 , wherein Link 1 is formed from a compound selected from the group consisting of: ethylene glycol; butane diol; hexane diol; hexamethylene diol; 1,5-pentanediol; 2,2-dimethyl-1,3 propanediol; 1,4-cyclohexane diol; 1,4-cyclohexanedimethanol; tri(ethylene glycol); poly(ethylene glycol), where the molecular weight is between 100 and 2000 Daltons; poly(ethylene oxide) diamine, where the molecular weight is between 100 and 2000 Daltons; lysine esters; silicone diols; silicone diamines; polyether diols; polyether diamines; carbonate diols; carbonate diamines; dihydroxy vinyl derivatives; dihydroxydiphenylsulfone; ethylene diamine; hexamethylene diamine; 1,2-diamino-2-methylpropane; 3,3-diamino-n-methyldipropylamine; 1,4-diaminobutane; 1,7-diaminoheptane; and 1,8-diaminooctane.
20 . The article of claim 19 , wherein Link 1 is formed from tri(ethylene glycol).
21 . The article of any one of claims 1 - 15 , wherein Link 1 is formed from a dicarboxylic compound or a diisocyanate.
22 . The article of any one of claims 1 - 3 and 7 - 15 , wherein Bio 2 is absent, and Link 1 is formed from a monoalcohol or a monoamine.
23 . The article of claim 1 or 2 , wherein m is 1, Bio 1 and Bio 2 are both formed from ciprofloxacin, and Link 1 is formed from tri(ethylene glycol).
24 . The article of claim 1 or 2 , wherein m is 1, Bio 1 is formed from ciprofloxacin, Bio 2 is absent, and Link 1 is formed from tri(ethylene glycol).
25 . The article of any one of claims 1 - 24 , wherein said coating comprises a second compound having a structure according to formula (I) or formula (I-A), wherein each Bio 1 , Link 1 , and Bio 2 is as defined in any of claims 1 - 19 .
26 . The article of any one of claims 1 - 25 , wherein said coating is substantially free of any biologically active agent used to form Bio 1 and/or Bio 2 , wherein the biologically active agent is not included in a compound according to formula (I).
27 . The article of any one of claims 1 - 25 , wherein said coating further comprises free biologically active agent, wherein the mole ratio of the compound according to formula (I) to the free biologically active agent is from 0.1:1 to 1:0.1.
28 . The article of any one of claims 1 - 27 , wherein said compound according to formula (I) has reduced biological activity compared to the biologically active agent used to form Bio 1 and/or Bio 2 .
29 . The article of claim 28 , wherein said compound according to formula (I) or formula (I-A) has 0%-20% of the biological activity of the biologically active agent used to form Bio 1 and/or Bio 2 .
30 . The article of any one of claims 1 - 29 , wherein said coating comprises a pharmaceutically acceptable salt of the compound according to formula (I) or formula (I-A).
31 . The article of claim 30 , wherein said pharmaceutically acceptable salt is the trifluoroacetate or the hydrochloride salt.
32 . The article of any of claims 1 - 31 , wherein said article is a filter, film, fiber, sheet, or an implantable medical device.
33 . The article of claim 32 , wherein implantable device is selected from: prostheses pacemakers, electrical leads, defibrillators, artificial hearts, ventricular assist devices, anatomical reconstruction prostheses, artificial heart valves, heart valve stents, pericardial patches, surgical patches, coronary stents, vascular grafts, vascular and structural stents, vascular or cardiovascular shunts, biological conduits, pledges, sutures, annuloplasty rings, stents, staples, valved grafts, dermal grafts for wound healing, orthopedic spinal implants, orthopedic devices, ophthalmic implants, intrauterine devices, stents, maxial facial reconstruction plating, dental implants, intraocular lenses, clips, sternal wires, bone, skin, ligaments, sutures, hernia mesh, tendons, and combinations thereof
34 . The article of claim 32 , wherein
said article is a percutaneous device selected from: catheters, cannulas, drainage tubes, and surgical instruments, or said article is a cutaneous device selected from burn dressings, wound dressings, and dental hardware.
35 . The article of claim 34 , wherein said surgical instrument is selected from: forceps, retractors, needles, gloves, and catheter cuffs.
36 . The article of claim 35 , wherein said article is a catheter cuff.
37 . The article of any one of claims 1 - 36 , wherein said coating has a thickness between 0.5 to 120 μM.
38 . The article of any one of claims 1 - 37 , wherein said article comprises a fibrous polymer matrix comprising the compound or compounds according to formula (I) and/or formula (I-A).
39 . The article of any one of claims 1 - 31 , wherein said article comprises a mixture of two or more compounds according to formula (I) and/or formula (I-A).
40 . The article of claim 38 , wherein said polymer matrix is formed from a biodegradable polymer.
41 . The article of claim 40 , wherein said polymer is polylactic acid, polycaprolactone, or polyurethane.
42 . The article of claim 38 , wherein said polymer matrix is formed from a nonbiodegradable polymer.
43 . The article of claim 42 , wherein said polymer is poly(ethylene terephthalate).
44 . The article of claim 33 , wherein said article is a catheter cuff.
45 . The article of claim 44 , wherein said catheter cuff is a vascular access catheter cuff.
46 . The article of claim 43 , wherein said article is an orthopedic device.
47 . The article of claim 46 , wherein said orthopedic device is a wire, pin, rod, nail, screw, disk, plate, bracket, or splint.
48 . The article of claim 33 , wherein said ophthalmic implant is a punctal plug.
49 . A method of preventing infection in a subject in need thereof, said method comprising implanting a device comprising a coated surface, wherein said coated surface comprises a compound having a structure according to formula (I):
Bio 1 -Link 1 -(Bio 2 -R 1 ) m (I),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; m is 1, 2, 3, 4, or 5; each Bio 2 is absent or independently formed from a biologically active agent, and wherein each Bio 2 , when present, comprises a covalent bond to Link 1 ; R 1 is present only when Bio 2 is absent and is a terminal group selected from the group consisting of H, OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; and Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60-2000 Daltons.
50 . The method of claim 49 , wherein said compound has a structure according to formula (I-A),
Bio 1 -Link 1 -Bio 2 -R 1 (I-A),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; Bio 2 is absent or formed from a biologically active agent; R 1 , when present, is H, OH, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; and Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60-2000 Daltons.
51 . The method of claim 49 or 50 , wherein said compound is the compound of any one of claims 3 - 38 .
52 . An admixture comprising a base polymer and a compound having a structure according to formula (I),
Bio 1 -Link 1 -(Bio 2 -R 1 ) m (I),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; m is 1, 2, 3, 4, or 5; each Bio 2 is absent or independently formed from a biologically active agent, and wherein each Bio 2 , when present, comprises a covalent bond to Link 1 ; R 1 is present only when Bio 2 is absent and is represents a terminal group selected from the group consisting of H, OH, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy; Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons.
53 . The admixture of claim 52 , wherein said compound has a structure according to formula (I-A),
Bio 1 -Link 1 -Bio 2 -R 1 (I-A),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; Bio 2 is absent or formed from a biologically active agent; R 1 , when present, is H, OH, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; and Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons.
54 . The admixture of claim 52 or 53 , wherein said compound is the compound of any one of claims 3 - 28 .
55 . The admixture of any one of claims 52 - 54 , wherein said admixture is a polymer matrix.
56 . A method for coating a surface with a composition, said composition comprising:
(a) a compound having a structure according to formula (I),
Bio 1 -Link 1 -(Bio 2 -R 1 ) m (I),
or a pharmaceutically acceptable salt thereof, wherein
Bio 1 is formed from a biologically active agent;
m is 1, 2, 3, 4, or 5;
each Bio 2 is absent or independently formed from a biologically active agent, and wherein each Bio 2 , when present, comprises a covalent bond to Link 1 ;
R 1 is present only when Bio 2 is absent and is represents a terminal group selected from H, OH, optionally substituted C1-C6 alkyl, or optionally substituted 01-C6 alkoxy;
Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons
and
(b) a suitable medium in which the compound of (a) is soluble; and
said method comprising contacting the surface with said composition.
57 . The method of claim 56 , wherein said compound has a structure according to formula (I-A),
Bio 1 -Link 1 -Bio 2 -R 1 (I-A),
or a pharmaceutically acceptable salt thereof, wherein Bio 1 is formed from a biologically active agent; Bio 2 is absent or formed from a biologically active agent; R 1 , when present, is H, OH, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; and Link 1 is an oligomeric organic, organosilicon, or organosulfone segment having a molecular weight between 60 and 2000 Daltons.
58 . The method of claim 56 or 57 , wherein said compound is as set forth in any of claims 3 - 28 .
59 . The method of any one of claims 56 - 58 , wherein (b) is an organic solvent or aqueous solvent.
60 . The method of claim 59 , wherein said polar organic solvent is tetrahydrofuran or N,N-dimethylformamide.
61 . The method of claim 59 or 60 , wherein the concentration of (a) is between 0.05-150 mg/mL.
62 . The method of claim 59 or 60 , wherein said article comprises a mixture of two or more compounds according to formula (I) and/or formula (I-A).
63 . The method of claim 59 or 60 , wherein one or both of Bio 1 and Bio 2 , when present, is formed from an anti-microbial agent.
64 . The method of claim 59 or 60 , wherein Bio 1 is formed from a first biologically active agent, and Bio 2 , when present, is formed from a second biologically active agent.
65 . The method of claim 64 , wherein said first biologically active agent is an antibiotic.
66 . The method of claim 64 or 65 , wherein said second biologically active agent is an antibiotic.
67 . The method of claim 65 or 66 , wherein said first antibiotic is a fluoroquinolone antibiotic.
68 . The method of any one of claims 65 - 67 , wherein said second antibiotic is a fluoroquinolone antibiotic.
69 . The method of any one of claims 66 - 68 , wherein said first antiobiotic is same as said second antibiotic.
70 . The method of claim any one of claims 67 - 69 , wherein said antibiotic is selected from the group consisting of: norfloxancin, oflxacin, ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin.
71 . The method of claim 70 , wherein said antibiotic is ciprofloxacin.Cited by (0)
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